Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation
Open accessAbstract
cAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein β-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.
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Inflammation reduces the ability of DISC1 to anchor PDE4A via increases in MK2 signaling.
“The onset of schizophrenia is associated with signs of increased inflammation and PFC gray matter loss5, and biochemical studies in vitro have shown that inflammation reduces the ability of DISC1 to anchor PDE4A via increases in MK2 signaling125 (Fig. 4, purple).”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [125]
The section on PDE4A5 co-immunoprecipitation with DISC1 (page not supplied) reports that anisomycin-treated cells showed less DISC1 bound to PDE4A5, an effect absent when MK2 activation was blocked. This supports the MK2-dependent loss of interaction, but the DISC1 experiment did not test inflammation itself; calling inflammation the demonstrated cause extends beyond that result. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInflammation may unanchor residual PDE4A and further disinhibit stress signaling pathways.
“Aβ fibrils also increase inflammation148 (Fig. 5, purple), which may unanchor residual PDE4A125, and further disinhibit stress signaling pathways.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [125]
The Results section reports that MK2 activation reduced PDE4A5 association with the scaffold protein DISC1, and the Discussion says MK2 phosphorylation weakens its interactions with DISC1 and AIP. The paper also notes that MK2 becomes activated during inflammation, supporting the proposed unanchoring mechanism. It does not examine residual PDE4A during Aβ-associated inflammation or show that this change disinhibits stress signaling pathways. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAge-related increases in inflammation may unanchor PDE4A.
“Studies of the aging monkey cortex have found that PDE4A is lost from these spines with advancing age, perhaps as a result of age-related increases in inflammation that may unanchor PDE4A125.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [125]
The Results section (page unavailable) reports that MK2 activation reduced PDE4A5 binding to the scaffold protein DISC1, supporting a possible mechanism for PDE4A5 becoming unanchored. The Discussion links MK2 activation to inflammatory signaling. The paper does not establish that age-related inflammation causes PDE4A loss from spines in the aging monkey cortex. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDISC1 anchors the phosphodiesterases (PDE4s) that catabolize cAMP and regulate its signaling.
“Particularly relevant to stress signaling in PFC, DISC1 anchors the phosphodiesterases (PDE4s) that catabolize cAMP and regulate its signaling121,125.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [125]
DISC1 is critical for regulation of the stress response in PFC.
“Emerging data indicate that the scaffolding protein Disrupted In Schizophrenia 1 (DISC1) is critical for regulation of the stress response in PFC, suggesting that genetic insults that interfere with the function of this protein increase the risk for stress-related psychiatric disorders.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [125]
The section on PDE4A5 interactions identifies DISC1 as a scaffolding protein and schizophrenia risk factor and reports reduced DISC1–PDE4A5 binding after anisomycin treatment. The Abstract discusses stress-response signaling generally, but neither passage addresses whether DISC1 is critical for regulating the stress response in the prefrontal cortex. Searches for DISC1 with PFC, stress response, and psychiatric risk found no passage establishing that point. (LLM, conf=0.76)
Experimental — accuracy not yet measured
PDE4A is lost from spines in the aging monkey cortex.
“Studies of the aging monkey cortex have found that PDE4A is lost from these spines with advancing age, perhaps as a result of age-related increases in inflammation that may unanchor PDE4A125.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [125]
The Discussion (page not provided) discusses PDE4A5 regulation, inflammation, and sleep-deprivation-related changes in the hippocampus, but not aging monkey cortex. A search for aging, monkey cortex, and loss of PDE4A from spines found no passage addressing that claim. (LLM, conf=0.76)
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Research works printed but not linked: 15
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- Authors
- MacKenzie, K. F., Wallace, D. A., Hill, E. V., Anthony, D. F., Henderson, D. J. P., Houslay, D. M., Arthur, J. S. C., Baillie, G. S., & Houslay, M. D.
- Affiliations
- University of Glasgow (GB)
- University of Dundee (GB)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2011-04-13
- Volume
- 435
- Issue
- 3
- Pages
- 755-769
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W1986544016
- Cited by
- 65
- References
- 0
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 2 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 9 · 2013: 2 · 2012: 3
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- European Commission (037189, LSHB-CT-2006-037189)
- Fondation Leducq (06CVD02)
- Medical Research Council (G0600765)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- phosphodiesterase 4, MAPKAPK2, protein phosphorylation, protein kinase A, cAMP signaling, p38 MAPK, macrophages, DISC1, AIP, beta-arrestin, protein-protein interaction
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Animals, Chlorocebus aethiops, HeLa Cells, Humans, Phosphorylation, Substrate Specificity, Protein Serine-Threonine Kinases, Cyclic AMP-Dependent Protein Kinases, COS Cells, Intracellular Signaling Peptides and Proteins, Mice, Cyclic Nucleotide Phosphodiesterases, Type 4
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